Precocious puberty is a common developmental abnormality of the pediatric endocrine system. In order to standardize the diagnosis and treatment of central (true) precocious puberty, the Endocrine Genetic Metabolism Group of the Pediatrics Branch of the Chinese Medical Association conducted a special discussion and formulated the following guidelines for clinical reference.
[Definition]
Precocious puberty is a developmental abnormality in which girls present secondary sexual characteristics by the age of 8 years and boys by the age of 9 years. CPP is also known as GnRH-dependent precocious puberty, which develops progressively until the development of the reproductive system is mature.
[Etiology]
1, Organic lesions of the central nervous system.
2. Peripheral precocious puberty is transformed.
3. Idiopathic CPP (ICPP) without organic lesions. About 80%-9o% of female children have ICPP, while more than 80% of male children have the opposite organic nature.
[Diagnosis
We should first determine whether the child has GnRH-dependent precocious puberty, and then make a differential diagnosis of the cause.
I. Diagnostic basis
1. Early appearance of secondary sexual characteristics: before 8 years old in girls and before 9 years old in boys.
2. Elevated serum gonadotropin levels up to puberty level.
(1) Basal gonadotropin value: If the secondary sexual characteristics have reached the level of mid-puberty, the basal serum luteinizing hormone (Ia-I) value can be used as the initial screening, such as >5.0 IU/L, it can be determined that the gonadal axis has been launched, and there is no need to conduct gonadotropin-releasing hormone (GnRH) stimulation test.
(2) GnRH excitation test: This test is an important diagnostic tool for those whose gonadal axis function has been initiated but whose gonadotropin base value is not elevated, GnRH can increase gonadotropin secretion and release, and its excitation peak can be used as a diagnostic basis. The synthetic GnRH analogue (GnRHa) has a stronger stimulatory effect than the natural one, with a peak at 60-120 rain, but its use in routine diagnosis is not recommended.
The cut-point value of LH excitation peak for the diagnosis of CPP: depends on the method of gonadotropin detection used, when measured by radioimmunoassay, LH peak should be >12.0 IU/L in girls and >25.0 IU/L in boys, LH~[/FSH peak >0.6-1.0 can diagnose CPP; when measured by immunochemiluminescence assay (ICMA), LH peak >5.0 IU/L, LH~[/FSH peak >0.6 (both sexes) can be diagnosed CPP; such as LH~/rSH peak >0.3, but 1 ml, and multiple follicles >4 mm in diameter can be seen; testicular volume in boys ≥4 ml, and with the prolongation of the disease is progressively increasing.
4, Linear growth was accelerated.
5, Bone age exceeds age by 1 year or more.
6.Serum sex hormone levels are elevated to pubertal levels.
Among the above diagnostic bases, 1, 2 and 3 are the most important and must be available. However, if the duration of the disease at the time of consultation is very short, the GnRH excitation value may overlap with the prepubertal value and not reach the above diagnostic cut-off value; the same applies to the ovarian size. Such children should be followed for paraphimosis progression and linear growth acceleration and the above tests should be repeated if necessary. In female children, linear growth acceleration during puberty usually occurs about 6 months to 1 year after the onset of breast development (B to B, stage) and lasts for 1 to 2 years; however, there are some late cases, even about 5% of children present one year before or in the year of menarche. In boys, accelerated growth occurs when the testicular volume is about 8 to 10 ml or one year before the change of voice, and lasts longer than in girls. The advancement of bone age only indicates the increase of sex hormone level for a period of time, which is not a specific indicator for the diagnosis of CPP. Children with short duration of disease and slow development process may not have obvious advancement of bone age, while peripheral precocious puberty may also have advancement of bone age; elevated sex hormone level cannot distinguish between central and peripheral precocious puberty.
In conclusion, the diagnosis of CPP is comprehensive, and the core issue is that it must be GnRH-dependent, and the progressive development of sexual characteristics in clinical follow-up is of great significance.
Etiological diagnosis
We should pay attention to collecting medical history related to the etiology of CPP, such as infection, central nervous system lesions and other related symptoms; all children diagnosed with CPP should exclude tumors, and MRI or CT examination of the cranial saddle area is needed; MRI has better resolution than CT for organic lesions of hypothalamus and pituitary gland.
Differential diagnosis
Although GnRH excitation test can largely identify central precocious puberty and peripheral precocious puberty, the following conditions should be identified.
1. simple precocious breast development: i.e., partial central precocious puberty (PICPP), where FSH is significantly elevated after GnRH excitation (it is also elevated after excitation in normal prepubertal girls), but LH elevation is not significant (mostly 1. However, it is noteworthy that PICPP is converted to CPP in the absence of any clinical precursor manifestations. therefore, regular follow-up is required after the diagnosis of PICPP, especially for those with recurrent breast enlargement or persistent non-receding, repeat the provocation test if necessary.
2, CPP transformed from non-central precocious puberty such as congenital adrenocortical hyperplasia, MeCune?Albright syndrome, etc., must be monitored during the treatment of the primary disease.
In this case, the child with congenital hypothyroidism with precocious puberty is a special type of precocious puberty, in which the basal blood LH value is elevated in the early stage, but not after GnRH excitation, and only after a longer course of the disease is it transformed into true CPP. short stature is an important feature.
[Pharmacological treatment]
The treatment of CPP is focused on improving the adult height of the child, and attention should be paid to prevent the psychological problems associated with premature maturation and early menarche. GnRH analogues (gonadotroping releasing hormone analogue (GnRHa)) are generally used to treat CPP, and the slow-release GnRHa preparations currently available for children in China are Triptorelin and Leuprorelin acetate; the former is Decapeptyl Dep and Diphereline; the latter is Enanteline. GnRI-Ia can effectively inhibit the secretion of LH, causing the gonads to suspend development and the secretion of sex hormones to return to the prepubertal state, thus delaying the growth and fusion of the epiphysis and achieving the purpose of extending the growth years and improving the final height in adulthood as much as possible.
I. Indications for the application of GnRHa
1, in order to achieve the purpose of improving the lifelong height in adulthood, the applicable indications for children with significantly impaired growth potential and at the same time there is residual growth potential, that is, the bone age is significantly ahead of the epiphysis has not yet begun to fuse, the specific recommendations are as follows: (1) bone age bone age ≥ 2 years; girls ≤ 11.5 years, boys ≤ 12.5 years. (2) Predicted height in adulthood girls 1, or height SDS1 judged by bone age.
2. Indications for caution.
The efficacy of improving adult height is poor when the following conditions exist and should be used with caution as appropriate.
(1) Bone age >11.5 years for girls and >12.5 years for boys at the start of treatment.
(2) Those whose genetic target height is 2 standard deviations below the normal reference value (one 2SDS). Other causes of short stature should be considered.
3. Indications for inappropriate application.
GnRHa treatment alone is not effective in improving height in adulthood in those with the following conditions.
(1) bone age of girls ≥ 12.5 years, boys ≥ 13.5 years.
(2) 1 year after menarche in girls or after ejaculation in boys.
4, does not need to apply the indications.
(1) sexual maturation process is slow (bone age progression does not exceed age progression) does not require treatment when the impact on adult height is small.
(2) Although the bone age is advanced, the height growth rate is fast, so that the height age is greater than the bone age and the predicted height in adulthood is not impaired. However, because the process of pubertal maturation is dynamic, the judgment of each individual should also be dynamic. Once the diagnosis of CPP is established, those whose initial assessment is deemed temporarily not to require treatment are required to periodically review their height and bone age changes, periodically re-evaluate the need for treatment, and develop treatment plans as needed.
Second, GnRHa application methods
1, the dose: the first dose of 80-100 g/kg, 2 weeks later to strengthen 1, after every 4 weeks 1 (not more than 5 weeks), the dose of 60-80 g/kg, the dose needs to be individualized, according to the gonadal axis function inhibition (including sex characteristics, sex hormone levels and bone age progress), poor inhibition can refer to the first dose, the maximum amount of 3.75 ms / times. In order to know exactly the bone age progression, clinicians should personally evaluate and compare the bone age before and after treatment, and should not make judgment only by the radiology report.
2. Monitoring during treatment: check the secondary sexual characteristics and measure height every 2-3 months during treatment; review the GnRH excitation test at the end of 3 months after the first dose, if the LH excitation value is in the prepubertal value, it means the dose is appropriate; thereafter, only the basal serum estradiol (E) concentration or vaginal smear (maturation index) should be reviewed regularly for girls, and the basal serum testosterone should be reviewed for boys. In boys, the basal serum testosterone levels were reviewed to determine the suppression of gonadal axis function. Bone age should be reviewed every 6 to 12 months, and ultrasound of the uterus and ovaries should be reviewed in girls.
3, the course of treatment: in order to improve adult height, the course of GnRHa generally need at least 2 years, girls in the bone age of 12.0 ~ 12.5 years should stop treatment, at this time, such as extending the course of treatment is often difficult to continue to improve the height of adulthood. For those who start treatment at a younger age, if their age has caught up with the bone age, and the bone age has reached the normal pubertal initiation age (t>8 years), the predicted height can reach the genetic target height can stop the drug, so that the gonadal axis function restart, should be followed up regularly.
Third, the monitoring after discontinuation of the drug
The height, weight and recovery of paraphilias as well as the recovery of gonadal axis function should be reviewed every six months after the end of treatment. Girls usually present menarche within 2 years after stopping treatment.
Fourth, the treatment of growth deceleration in GnRHa treatment
The growth rate of the first six months of GnRHa treatment does not change significantly compared with that before treatment, and after six months it generally falls back to the growth rate of pre-puberty (about 5 cm/year), and the growth rate of some children after 1 to 2 years of treatment.